What prevents cardioprotective drugs from reaching the market?

KEYWORDS:

• Cardioprotection
• cardiovascular drugs
• market
• clinical trials
• cardiovascular event
• mortality

1. Introduction

The term cardioprotection has a bivalent meaning. In the current language, protection means helping someone to gain an advantage or better position. In the biological sense, protection expresses the natural adaptive mechanisms or therapeutic interventions preventing damage to tissues and systems [1]. From the pharmacological point of view, ‘cardiovascular protection’ represents preserving the metabolism, structure, and function of the heart and vasculature and limiting their damage either in primary or secondary prevention.

Some 50 years ago, the term cardioprotection was almost exclusively associated with ischemic heart disease, myocardial infarction, or reperfusion damage. Since the beginning of the nineties, when the effectiveness of heart failure (HF) treatment started to be investigated in clinical trials, the term cardioprotection has meant protection of an ischemic, hypertensive and failing heart or a heart damaged by antineoplastic therapy. Vascular protection is aimed at the preservation of endothelial function, attenuation of vascular stiffening, and predominantly on reducing atherosclerosis progression and complications. The principle objective of evidence-based medicine is not simply the improvement of symptoms but the reduction of cardiovascular events and death. However, this is a difficult task. Several groups of drugs such as angiotensin converting enzyme inhibitors (ACEIs), blockers of receptors for angiotensin II type one (ARBs), beta-blockers (BBs), aldosterone receptor blockers (AlRBs), statins and antiaggregatory and anticoagulatory treatment were shown to be effective in achieving the hard endpoints; however, mortality reduction with most drugs does not exceed 30% and the residual cardiovascular risks remain high. Thus, the search for novel approaches within cardiovascular protection remains unremitting.

In questioning what prevents cardiovascular protectives from reaching the market, it might be reasonable to consider two distinct issues: What prevents cardiovascular drugs that are evidently beneficial in one cardiovascular disease from being approved as protective in another promising indication? What prevents the substances showing protection in animals or smaller clinical experiments from reaching the market as cardiovascular protectives?

2. What prevents cardiovascular drugs that are beneficial in one cardiovascular pathology from reaching the market in another promising indication?

Developing a new drug and testing it from the level of experiments on cultures and small animals up to the point of significant benefit in large clinical trials is laborious and financially demanding. Large clinical trials involve several thousands of patients, are double blind, randomized, and mostly multicentric, and are designed and controlled by influential experts in the field. The drugs with significant clinical benefit represent only a fraction of substances being investigated. Thus, to test drugs with proven cardiovascular protection in one indication in another cardiovascular disease seems to be a rational and hopeful strategy.

Remarkable success with this approach has been achieved. ACEIs were introduced in the treatment of hypertension and later became the cornerstone of HF treatment [2,3]. Similarly, AlRB spironolactone, which was originally used as a potassium sparing diuretic in hypertension, prominently reduced mortality, when added to standard treatment in patients with severe HF [4]. Statins exert morbidity and mortality benefit in both primary and secondary prevention by lowering the high level of low-density lipoprotein (LDL)-cholesterol. Atorvastatin was later shown to reduce cardiovascular events in hypertensive patients with average LDL but increased cardiovascular (CV) risk [5] and in patients with acute myocardial infarction [6]. BBs along with the diuretics were the first drugs with a proven mortality benefit in hypertensive patients, and BBs were later confirmed to convincingly reduce mortality in HF patients [7]. Reduction of heart remodeling, improvement of its energetic state, and prevention of atherosclerotic complications by plaque stabilization stand in the pathophysiological background of these exciting outcomes.

On the other hand, well-established protectives failed to fulfill expectations in some indications:

- Statins exert a number of pleiotropic actions. In animal and humans experiments, statins reduced fibrosis and left ventricular hypertrophy in hypertensive and failing heart [8]. However, they failed to reduce morbidity and mortality in patients with HF and are not recommended for HF treatment [7]. The reversal epidemiology of lowering the LDL-cholesterol level in the elderly with HF might have participated on the undesirable outcomes of statins in failing heart patients.

- Increased heart rate (HR) is a well-documented but neglected cardiovascular risk factor among healthy individuals and patients with ischemic heart disease (IHD), HF, or hypertension. In IHD and HF, the bradycardic effect is considered the principle mechanism of the benefit of BBs via the improvement of the supply-demand balance. However, in hypertensive patients with elevated HR, BBs did not show any additional benefit of elevated HR reduction to the BP decrease, and the pharmacotherapy of these patients remains to be established [9,10]. The lack of effect of BBs on aortic blood pressure might be considered as a pathophysiologic mechanism of this neutral finding with BBs in hypertension.

- Phosphodiesterase inhibitors with prominent positive inotropic effects such as amrinone, milrinone, or vesnarinone consistently increased mortality rate when applied to patients with chronic HF with reduced ejection fraction [11] and are no longer used in this indication. The toxic effect of calcium overload resulting in heart muscle cell damage or fatal dysrhythmia could explain the deleterious effect of positive inotropy in HF patients. Surprisingly, trials with calcium-channel blockers (CCBs) reducing the entrance of calcium ions into heart muscle cells did not show beneficial effect in HF, and are not recommended in symptomatic patients with HF with reduced ejection fraction [7]. The increase in sympathetic tone (in some dihydropyridine CCBs) might contribute to the unsafe profile in patients with HF.

- A number of experiments have confirmed that lethal ischemia-reperfusion injury is tightly bound to mitochondrial permeability transition pore opening, which can be prevented by cyclosporine A. However, the use of cyclosporine at the time of primary percutaneous coronary angioplasty in trials with segment (ST) elevation myocardial infarction patients showed the absence of any benefit regarding the all-cause and cardiovascular mortality or hospital readmission for HF [12]. The inappropriate time and dose of drug application or the simplified insight on the pathomechanism of reperfusion injury might have participated on the failure of cyclosporine and several other potentially protective substances in ischemia-reperfusion protection.

Taken together, the failure of trials involving an established cardiovascular drug in a novel indication may prevent it from reaching the market in this particular condition.

3. What prevents substances that show cardiovascular protection in animals or in smaller clinical experiments from reaching the market?

Many natural substances are being tested on animals or a small number of patients, and coenzyme Q10 and melatonin rank among the most hopeful substances. Melatonin, a hormone produced mainly in the pineal gland at night, exerts a number of potentially beneficial actions on the cardiovascular system. In addition to its chronobiologic effect exerting circadian variations of many physiologic actions, this indoleamine has prominent antioxidant and scavenging effects both extracellularly and intracellularly [13], as well as anti-inflammatory and antiapoptotic effects. These properties are projected in sympatholytic action, improved endothelial function, reduction of blood pressure and HR and attenuation of fibrosis in hypertensive and failing heart [14–16]. Similarly, coenzyme Q10, as a natural substance being an important part of the mitochondrial respiratory chain, improves the energetic state of cardiovascular tissues and reduces free radical burden [17]. Both substances seem to be safe, with minimal or no side effects and are easily available. Although the benefit in terms of improvement in surrogate endpoints was convincingly demonstrated in a number of cardiovascular pathologies in animals, only smaller groups of patients have confirmed the clinical benefits. The reluctance to perform large clinical trials with these and many similar substances which might open their way on the market may be due to several interrelated factors:

-First, testing on animals has limitations. The number of individuals per group is relatively small and never reaches a size comparable with clinical trials. The HR in small animals is well above 300 beats per minute and energy demands are many times higher than in adult men. The pharmacological doses of drugs that are tested exceed by several times the dose recommended in patients. Moreover, instead of mortality rate the surrogate endpoints or biomarkers are frequently investigated [18,19].

-Second, most natural substances like coenzyme Q10, melatonin, and plant extracts are freely available on the pharmaceutical market as food supplements without any protection by a pharmaceutical firm. Without the financial support of the pharmaceutical industry, it is almost impossible to perform large multicentric trials.

-Third, the interest of any institution in potentially being able to support the research is limited by the fact that nowadays there are many proven therapies for any current cardiovascular pathology. Thus, a promising substance is not being compared with a placebo but with a well-established drug or even a group of them. Since our pathophysiologic insights into the mechanisms of a particular disease are restricted, the probability of achieving additional benefits to well-established treatment is rather small.

Several potential approaches should be adopted to improve the situation in the translational research in cardiovascular medicine [20,21]. To make the preclinical research more reliable and valuable, it is recommended to standardize protocols, introduce multicenter design, and register preclinical studies in an open database. Researchers and journals should consider to publish not only positive but also negative results and perform meta-analysis from similarly designed preclinical studies. Verification of positive outcomes on nonrodent species in a certified independent laboratory in a well-designed and robust preclinical experiment could not only confirm the pathophysiological insights but also reduce the disappointment in clinical studies.

4. What can be expected in the future?

The development of completely new protectives or even introducing natural substances into clinical practice will be more the exception than the rule [22]. Thus, the number of cardioprotectives in the market will also remain limited. Worldwide competition, restricted possibilities of investors, the existence of several established therapeutic means for the treatment of most cardiovascular disorders and the limited knowledge of pathophysiology will prevent a flurry of officially approved cardiovascular drugs on the market. However, the exploitation of the potential benefits of established cardiovascular therapeutics in untraditional cardiovascular indications will remain of utmost importance. The perspective of the day-to-day clinical approach to cardiovascular protection will include giving the patient everything that should be given, using the recommended doses and searching for optimal combinations. Despite the recommendations of guidelines, the space for a doctor’s thinking and individual approach remains large. As Saint Exupery said: ‘I admire the science but in the same way I admire the human wisdom.’

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the grants for scientific research VEGA 1/0071/15, VEGA 2/0195/15 and by the program PROGRES Q 40/5.